Clin Chem. 1976 Jun;22(6):777-81.
Gas-chromatographic analysis for therapeutic concentrations of amitriptyline and nortriptyline in plasma, with use of a nitrogen detector.

Bailey DN, Jatlow PI.

We describe a gas-chromatographic procedure for the simultaneous determination of amitriptyline and its active metabolite, nortriptyline, in therapeutic concentrations in human plasma, with use of a nitrogen detector. Both drugs are extracted at pH 10.5 into hexane/isoamyl alcohol, back-extracted into dilute HCl, and re-extracted into hexane/isoamyl alcohol after alkalinization of the HCl. The solvent is evaporated and the residue gas-chromatographed. Protriptyline is used as the internal standard. As little as 5 mug of amitriptyline or nortriptyline can be detected per liter of plasma. The coefficients of variation, for a concentration of 200 mug/liter, are 4.6% and 4.3% within-day and 8.6% and 3.4% day-to-day for amitriptyline and nortriptyline, respectively. The procedure was applied to patients receiving therapeutic doses of both drugs and also to patients who had taken overdoses of amitriptyline.

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Cephalalgia. 2003 Jun;23(5):367-75.
Selective decrease in serotonin synthesis rate in rat brainstem raphe nuclei following chronic administration of low doses of amitriptyline: an effect compatible with an anti-migraine effect.

Pringsheim T, Diksic M, Dobson C, Nguyen K, Hamel E.

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

The effects of chronic, low-dose amitriptyline on serotonin (5-HT) synthesis rate were measured in rat brain using autoradiography and the trapping of alpha-[14C]-methyl-L-tryptophan (alpha-[14C]-MTrp). Rats received amitriptyline (2 mg/kg per day) or saline via intraperitoneal osmotic minipumps for 21 days. Amitriptyline had no effect on any physiological parameters measured, or on free or total plasma tryptophan levels. However, amitriptyline exerted selective decreases of 15% and 17% (P < 0.001) in serotonin synthesis rates in the dorsal and median raphe nuclei, respectively. There was no reduction in any of the projection areas studied, including the cerebral cortex, hippocampus, thalamus, hypothalamus or striatum. The data suggest that chronic low doses of amitriptyline can lead to sustained 5-HT re-uptake inhibition selectively in the raphe nuclei, an effect compatible with tonic activation of 5-HT(1A) autoreceptors and inhibition of 5-HT synthesis. The failure of chronic amitriptyline treatment to affect 5-HT synthesis rate in the projection areas may ensure an adequate regulation of pain pathways implicated in migraine headache, an effect possibly related to amitriptyline anti-migraine efficacy.

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J Am Med Dir Assoc. 2002 Jan-Feb;3(1):5-11.
Urban-rural differences in amitriptyline use among nursing facility residents.

Rigler SK, Wallace D, Studenski S, Perera S, Brown EF, Redford L, Webb M.

Department of Internal Medicine, and Center on Aging, University of Kansas School of Medicine, Kansas City, Kansas 66160-7376, USA.

OBJECTIVE: To characterize patterns of amitriptyline use across the urban-rural continuum. DESIGN: Retrospective analysis of antidepressant drug codes and demographic and clinical data from the Minimum Data Set (MDS), 1994 to 1997. SETTING: Kansas nursing facilities. PARTICIPANTS: Facility residents aged 65 and older. MEASURES: A four-strata system was used to classify nursing facility location by county, from urban to frontier. We examined admission use and after-admission use of amitriptyline across strata for each year separately. Unadjusted and adjusted odds ratios were determined for each stratum, using the urban stratum as the point of reference. RESULTS: Admission use of amitriptyline occurred in 2.3 to 4% of all admissions, and although such use was highest in the most rural stratum, no clear urban-rural gradient was found. In contrast, amitriptyline use 30 days or more after admission demonstrated modest urban-rural gradients in unadjusted and adjusted analyses. In 1997, when adjusted for demographic factors, odds ratios for amitriptyline use were 2.10 (1.54-2.87), 1.68 (1.33-2.13), and 1.49 (1.17-1.90) for the Frontier, Rural, and Densely Settled Rural categories as compared with the Urban reference group. CONCLUSIONS: After admission to Kansas nursing facilities, rural practice patterns for amitriptyline use are less favorable than those in urban areas, and an urban-rural gradient is identified. Further work is needed to identify explanatory patient, facility, and prescriber factors.

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Anesth Analg. 2003 Jul;97(1):91-5, table of contents.
The relative toxicity of amitriptyline, bupivacaine, and levobupivacaine administered as rapid infusions in rats.

Srinivasa V, Gerner P, Haderer A, Abdi S, Jarolim P, Wang GK.

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Intravascular injection of local anesthetics carries the risk of cardiovascular (CV) and central nervous system (CNS) toxicity. Amitriptyline, a tricyclic antidepressant, has local anesthetic potency that is more than that of bupivacaine. In this study, we compared the CV and CNS toxicity of the local anesthetics bupivacaine and levobupivacaine with that of amitriptyline. Twenty-nine Sprague-Dawley rats had their right external jugular vein and carotid artery cannulated under general anesthesia. On Day 2, rats were sedated with midazolam (0.375 mg/kg intraperitoneally) and received rapid infusions of either 1) bupivacaine, levobupivacaine, or amitriptyline at 2 mg x kg(-1) x min(-1) (5 mg/mL concentration) or 2) normal saline (400 micro L x kg(-1) x min(-1)) through an external jugular vein cannula. Electrocardiogram and arterial blood pressure were measured until the dose to cause impending death was reached (heart rate 50 bpm/asystole or apnea for >30 s). The mean dose required to cause apnea and impending death was significantly larger for amitriptyline (74.0 +/- 21 mg/kg and 74.5 +/- 21 mg/kg, respectively) than for levobupivacaine (32.2 +/- 20 mg/kg and 33.9 +/- 22 mg/kg, respectively) or bupivacaine (21.5 +/- 7 mg/kg and 22.7 +/- 7 mg/kg, respectively) (P < 0.05). A significantly larger dose of amitriptyline, given by rapid infusion, is required to cause CV and CNS toxicity in rats, when compared with bupivacaine and levobupivacaine. IMPLICATIONS:Amitriptyline, a tricyclic antidepressant, has local anesthetic properties and is more potent than bupivacaine. Significantly larger doses of amitriptyline, given by rapid infusion, are required to cause cardiovascular and central nervous system toxicity in rats, when compared with bupivacaine and levobupivacaine.

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Anesth Analg. 2003 Jul;97(1):168-73, table of contents.
Peripheral antihyperalgesic and analgesic actions of ketamine and amitriptyline in a model of mild thermal injury in the rat.

Oatway M, Reid A, Sawynok J.

Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.

In this study, we examined antihyperalgesic and analgesic actions after local peripheral administration of ketamine and amitriptyline in a rat model of mild thermal injury. Exposure of the hindpaw to 52 degrees C for 45 s under anesthesia produced a subsequent thermal hyperalgesia lasting at least 2 h. The local peripheral administration of ketamine (100-1000 nmol) 15 min before the thermal injury produced an antihyperalgesic effect when injected into the ipsilateral paw, whereas amitriptyline produced both antihyperalgesic (300 nmol) and analgesic (1000 nmol) effects. Administered after the thermal injury, ketamine had no effect, whereas amitriptyline retained its analgesic but not its antihyperalgesic effect. Amitriptyline (300 and 1000 nmol) produced an analgesic action when administered into the normal nonsensitized hindpaw. Both drugs increase paw volume, particularly at larger doses; biogenic amines are not involved in the action of amitriptyline, as was shown previously for ketamine. These results indicate that (a) ketamine produces antihyperalgesia, but not analgesia, when administered locally with a mild thermal injury model; (b) amitriptyline produces both antihyperalgesia and analgesia when administered locally; and (c) the increase in paw volume produced by these drugs occurs by different mechanisms. IMPLICATIONS: This study examines the pain-relieving properties of the local peripheral administration of ketamine and amitriptyline, two drugs in current clinical use, in a thermal injury model of hyperalgesia and demonstrates both antihyperalgesic and analgesic properties. These observations provide support for their potential use as local (e.g., topical) analgesics.

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med.teikyo-u.ac.jp

The present study was undertaken to examine the effects of the antidepressant, amitriptyline, and brain-derived neurotrophic factor (BDNF) on activator protein-1 (AP-1) DNA binding activity in the rat brain. Acute administration of amitriptyline (5 or 10 mg/kg) initially increased but then decreased AP-1 DNA binding activity in the rat frontal cortex and hippocampus. Chronic administration of amitriptyline (5 or 10 mg/kg, once daily for 3 weeks) initially decreased AP-1 DNA binding activity but ultimately resulted in its persistent elevation in the rat frontal cortex. In contrast, the chronic administration of amitriptyline did not affect the low activity of AP-1 DNA binding in the hippocampus. However, chronic administration of amitriptyline (10 mg/kg, once daily for 3 weeks) significantly increased BDNF protein levels in the hippocampus (by 26.9%) and frontal cortex (by 24.6%). Direct infusion of BDNF (1 microg) into the hippocampal dentate gyrus significantly increased hippocampal AP-1 DNA binding activity. These results suggest that AP-1 transcription factor may be modulated by BDNF and that it may be an important target for the action of antidepressants.

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Bratisl Lek Listy. 1992 Nov;93(11):580-4.
[Adverse effects of antidepressive agents in hospitalized geriatric patients]

[Article in Slovak]

Korinkova V, Kolibas E, Kralova M, Novotny V, Konceoj VA, Pjatnickij AN, Andrusenkova MP.

Psychiatricka klinika LFUK a FN v Bratislave, CSFR.

The frequency, intensity and profile of adverse effects of antidepressants was studied in elderly patients. The series consisted of 102 patients with depression admitted to hospitals in Bratislava and Moscow. The adverse effects of amitriptyline (Amitriptylin Spofa) and maprotiline (Ludiomil Ciba-Geigy) were compared. The assessment done on days 0, 7, and 28 of treatment showed that xerostomia had the highest occurrence rate with both preparations studied. In patients treated with amitriptyline adverse effects were more severe and were recorded more frequently, requiring treatment withdrawal in 3 patients. The overall intensity of adverse effects was significantly higher with amitriptyline (p < 0.05). In the group of patients treated with amitriptyline the adverse effects were more marked in those with severe somatic pathology. The risk of amitriptyline treatment in elderly patients is being emphasized along with the need for monitoring and correcting adverse effects of the treatment. Although maprotiline exhibited a lower occurrence rate of adverse effects, cardiac functions should be regularly checked in patients with preexisting cardiac pathology. (Tab. 2, Fig. 3, Ref. 6.).

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